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Grant Details

Grant Number: 5R01CA114236-04 Interpret this number
Primary Investigator: Bernstein, Jonine
Organization: Sloan-Kettering Inst Can Research
Project Title: Breast Cancer, Radiation and the Atm-Chek2 Pathway
Fiscal Year: 2008


Abstract

DESCRIPTION (provided by applicant): All of the genes known to be associated with increased susceptibility to breast cancer function within a common biochemical pathway involved in signaling the presence of and responding to DNA double-strand breaks. Upon exposure to ionizing radiation (IR), ATM phosphorylates a large number of downstream targets, including the protein products of BRCA1 and CHEK2, in which specific mutations have been shown to predispose to breast cancer. Signaling between ATM and Chek2 involves at least five other proteins, p53 binding protein (53BP1), and MDC1, Mre11, RadSO, and Nbs1 (the latter three forming the MRN complex). To delineate the roles of radiation exposure and genetic predisposition in the etiology of breast cancer, we propose a case-control association study to examine the interaction of IR exposure with genetic variation in these genes in a population-based sample of young women with bilateral and unilateral breast cancer. Our study hypothesis is that the incidence of contralateral breast cancer will be increased among women who carry mutant alleles, alone, or in combination with one another, and who received radiation therapy as part of their treatment for first primary breast cancer. To carry out the current proposal, we will use the 2100 cases and controls from our multi-center WECARE Study and access the already established comprehensive data and biorepository that includes, for all study participants, epidemiologic data, biological specimens, treatment records, radiation dosimetry, and ATM, BRCA1 and BRCA2 mutation carrier status. Our specific aims are: Aim #1. Identify haplotype block structures and tagging SNPs for CHEK2, TP53BP1, MDC1, MRE11, RAD50 and NBS1. Aim #2. Genotype all 2100 WECARE Study participants (700 triplets) using SNPs identified in Aim #1 and selected based on haplotype analysis of sequenced samples. Aim #3. Conduct a population-based case-control association study of 6 genes involved in the ATM-CHEK2 pathway to determine whether they are associated with an increased risk of radiation-induced contralateral breast cancer.



Publications

Machine learning on genome-wide association studies to predict the risk of radiation-associated contralateral breast cancer in the WECARE Study.
Authors: Lee S. , Liang X. , Woods M. , Reiner A.S. , Concannon P. , Bernstein L. , Lynch C.F. , Boice J.D. , Deasy J.O. , Bernstein J.L. , et al. .
Source: PloS one, 2020; 15(2), p. e0226157.
EPub date: 2020-02-27.
PMID: 32106268
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CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study.
Authors: Brooks J.D. , Comen E.A. , Reiner A.S. , Orlow I. , Leong S.F. , Liang X. , Mellemkjær L. , Knight J.A. , Lynch C.F. , John E.M. , et al. .
Source: Breast cancer research : BCR, 2018-12-10; 20(1), p. 149.
EPub date: 2018-12-10.
PMID: 30526633
Related Citations

Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study.
Authors: Reiner A.S. , Sisti J. , John E.M. , Lynch C.F. , Brooks J.D. , Mellemkjær L. , Boice J.D. , Knight J.A. , Concannon P. , Capanu M. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018-05-20; 36(15), p. 1513-1520.
EPub date: 2018-04-05.
PMID: 29620998
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The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study.
Authors: Knight J.A. , Blackmore K.M. , Fan J. , Malone K.E. , John E.M. , Lynch C.F. , Vachon C.M. , Bernstein L. , Brooks J.D. , Reiner A.S. , et al. .
Source: Breast cancer research : BCR, 2018-03-22; 20(1), p. 23.
EPub date: 2018-03-22.
PMID: 29566728
Related Citations

Agreement between self-reported and register-based cardiovascular events among Danish breast cancer survivors.
Authors: Langballe R. , John E.M. , Malone K.E. , Bernstein L. , Knight J.A. , Lynch C.F. , Howell R.M. , Shore R. , Woods M. , Concannon P. , et al. .
Source: Journal of cancer survivorship : research and practice, 2018 02; 12(1), p. 95-100.
EPub date: 2017-09-29.
PMID: 28963606
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ATM, radiation, and the risk of second primary breast cancer.
Authors: Bernstein J.L. , WECARE Study Collaborative Group , Concannon P. .
Source: International journal of radiation biology, 2017 10; 93(10), p. 1121-1127.
EPub date: 2017-07-27.
PMID: 28627265
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Alcohol consumption and cigarette smoking in combination: A predictor of contralateral breast cancer risk in the WECARE study.
Authors: Knight J.A. , Fan J. , Malone K.E. , John E.M. , Lynch C.F. , Langballe R. , Bernstein L. , Shore R.E. , Brooks J.D. , Reiner A.S. , et al. .
Source: International journal of cancer, 2017-09-01; 141(5), p. 916-924.
EPub date: 2017-05-31.
PMID: 28524234
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Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population.
Authors: Reiner A.S. , Lynch C.F. , Sisti J.S. , John E.M. , Brooks J.D. , Bernstein L. , Knight J.A. , Hsu L. , Concannon P. , Mellemkjær L. , et al. .
Source: Breast cancer research : BCR, 2017-07-19; 19(1), p. 83.
EPub date: 2017-07-19.
PMID: 28724391
Related Citations

Body mass index, weight change, and risk of second primary breast cancer in the WECARE study: influence of estrogen receptor status of the first breast cancer.
Authors: Brooks J.D. , John E.M. , Mellemkjaer L. , Lynch C.F. , Knight J.A. , Malone K.E. , Reiner A.S. , Bernstein L. , Liang X. , Shore R.E. , et al. .
Source: Cancer medicine, 2016 11; 5(11), p. 3282-3291.
EPub date: 2016-10-03.
PMID: 27700016
Related Citations

Systemic therapy for breast cancer and risk of subsequent contralateral breast cancer in the WECARE Study.
Authors: Langballe R. , Mellemkjær L. , Malone K.E. , Lynch C.F. , John E.M. , Knight J.A. , Bernstein L. , Brooks J. , Andersson M. , Reiner A.S. , et al. .
Source: Breast cancer research : BCR, 2016-07-12; 18(1), p. 65.
EPub date: 2016-07-12.
PMID: 27400983
Related Citations

Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells.
Authors: Okamura T. , Antoun G. , Keir S.T. , Friedman H. , Bigner D.D. , Ali-Osman F. .
Source: The Journal of biological chemistry, 2015-12-25; 290(52), p. 30866-78.
EPub date: 2015-10-01.
PMID: 26429914
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Reproductive factors, tumor estrogen receptor status and contralateral breast cancer risk: results from the WECARE study.
Authors: Sisti J.S. , Bernstein J.L. , Lynch C.F. , Reiner A.S. , Mellemkjaer L. , Brooks J.D. , Knight J.A. , Bernstein L. , Malone K.E. , Woods M. , et al. .
Source: SpringerPlus, 2015; 4, p. 825.
EPub date: 2015-12-30.
PMID: 26751177
Related Citations

Breast-cancer risk in families with mutations in PALB2.
Authors: Antoniou A.C. , Casadei S. , Heikkinen T. , Barrowdale D. , Pylkäs K. , Roberts J. , Lee A. , Subramanian D. , De Leeneer K. , Fostira F. , et al. .
Source: The New England journal of medicine, 2014-08-07; 371(6), p. 497-506.
PMID: 25099575
Related Citations

Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: a WECARE study report.
Authors: Bernstein J.L. , Thomas D.C. , Shore R.E. , Robson M. , Boice J.D. , Stovall M. , Andersson M. , Bernstein L. , Malone K.E. , Reiner A.S. , et al. .
Source: European journal of cancer (Oxford, England : 1990), 2013 Sep; 49(14), p. 2979-85.
EPub date: 2013-05-21.
PMID: 23706288
Related Citations

Risk of asynchronous contralateral breast cancer in noncarriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: a report from the Women's Environmental Cancer and Radiation Epidemiology Study.
Authors: Reiner A.S. , John E.M. , Brooks J.D. , Lynch C.F. , Bernstein L. , Mellemkjær L. , Malone K.E. , Knight J.A. , Capanu M. , Teraoka S.N. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2013-02-01; 31(4), p. 433-9.
EPub date: 2012-12-26.
PMID: 23269995
Related Citations

Variation in genes related to obesity, weight, and weight change and risk of contralateral breast cancer in the WECARE Study population.
Authors: Brooks J.D. , Bernstein L. , Teraoka S.N. , Knight J.A. , Mellemkjær L. , John E.M. , Malone K.E. , Reiner A.S. , Lynch C.F. , Concannon P. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2012 Dec; 21(12), p. 2261-7.
EPub date: 2012-10-02.
PMID: 23033454
Related Citations

Reproductive status at first diagnosis influences risk of radiation-induced second primary contralateral breast cancer in the WECARE study.
Authors: Brooks J.D. , Boice J.D. , Stovall M. , Reiner A.S. , Bernstein L. , John E.M. , Lynch C.F. , Mellemkjær L. , Knight J.A. , Thomas D.C. , et al. .
Source: International journal of radiation oncology, biology, physics, 2012-11-15; 84(4), p. 917-24.
EPub date: 2012-04-06.
PMID: 22483700
Related Citations

Rare germline mutations in PALB2 and breast cancer risk: a population-based study.
Authors: Tischkowitz M. , Capanu M. , Sabbaghian N. , Li L. , Liang X. , Vallée M.P. , Tavtigian S.V. , Concannon P. , Foulkes W.D. , Bernstein L. , et al. .
Source: Human mutation, 2012 Apr; 33(4), p. 674-80.
EPub date: 2012-02-15.
PMID: 22241545
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Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study.
Authors: Brooks J.D. , Teraoka S.N. , Reiner A.S. , Satagopan J.M. , Bernstein L. , Thomas D.C. , Capanu M. , Stovall M. , Smith S.A. , Wei S. , et al. .
Source: Human mutation, 2012 Jan; 33(1), p. 158-64.
EPub date: 2011-09-29.
PMID: 21898661
Related Citations

Body mass index and risk of second primary breast cancer: the WECARE Study.
Authors: Brooks J.D. , John E.M. , Mellemkjær L. , Reiner A.S. , Malone K.E. , Lynch C.F. , Figueiredo J.C. , Haile R.W. , Shore R.E. , WECARE Study Collaborative Group , et al. .
Source: Breast cancer research and treatment, 2012 Jan; 131(2), p. 571-80.
EPub date: 2011-09-03.
PMID: 21892703
Related Citations

Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study.
Authors: Teraoka S.N. , Bernstein J.L. , Reiner A.S. , Haile R.W. , Bernstein L. , Lynch C.F. , Malone K.E. , Stovall M. , Capanu M. , Liang X. , et al. .
Source: Breast cancer research : BCR, 2011; 13(6), p. R114.
EPub date: 2011-11-17.
PMID: 22087758
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Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study.
Authors: Mellemkjaer L. , Dahl C. , Olsen J.H. , Bertelsen L. , Guldberg P. , Christensen J. , Børresen-Dale A.L. , Stovall M. , Langholz B. , Bernstein L. , et al. .
Source: British journal of cancer, 2008-02-26; 98(4), p. 728-33.
EPub date: 2008-02-05.
PMID: 18253122
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Effect of systemic adjuvant treatment on risk for contralateral breast cancer in the Women's Environment, Cancer and Radiation Epidemiology Study.
Authors: Bertelsen L. , Bernstein L. , Olsen J.H. , Mellemkjaer L. , Haile R.W. , Lynch C.F. , Malone K.E. , Anton-Culver H. , Christensen J. , Langholz B. , et al. .
Source: Journal of the National Cancer Institute, 2008-01-02; 100(1), p. 32-40.
EPub date: 2007-12-25.
PMID: 18159070
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The CHEK2*1100delC allelic variant and risk of breast cancer: screening results from the Breast Cancer Family Registry.
Authors: Bernstein J.L. , Teraoka S.N. , John E.M. , Andrulis I.L. , Knight J.A. , Lapinski R. , Olson E.R. , Wolitzer A.L. , Seminara D. , Whittemore A.S. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2006 Feb; 15(2), p. 348-52.
PMID: 16492927
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